Leukotriene antagonists containing tetrazolyl groups

ABSTRACT

This invention relates to alkanoic acid compounds having phenyl and heteroarylthio substituents which are useful as leukotriene antagonists and pharmaceutical compositions containing such compounds. This invention also relates to methods of treating diseases in which leukotrienes are a factor by administration of an effective amount of the above compounds or compositions.

This is a continuation of U.S. Ser. No. 07/066,592 filed Jun. 24, 1987,abandoned.

BACKGROUND OF THE INVENTION

"Slow Reacting Substance of Anaphylaxis" (SRS-A) has been shown to be ahighly potent bronchoconstricting substance which is released primarilyfrom mast cells and basophils on antigenic challenge. SRS-A has beenproposed as a primary mediator in human asthma. SRS-A, in addition toits pronounced effects on lung tissue, also produces permeabilitychanges in skin and may be involved in acute cutaneous allergicreactions. Further, SRS-A has been shown to effect depression ofventricular contraction and potentiation of the cardiovascular effectsof histamine.

The discovery of the naturally occurring leukotrienes and theirrelationship to SRS-A has reinforced interest in SRS-A and otherarachidonate metabolites. SRS-A derived from mouse, rat, guinea pig andman have all been characterized as mixtures of leukotriene-C₄ (LTC₄),leukotriene-D₄ (LTD₄) and leukotriene-E₄ (LTE₄), and structural formulaeof which are represented below. ##STR1##

Leukotrienes are a group of eicosanoids formed from arachidonic acidmetabolism via the lipoxygenase pathway. These lipid derivativesoriginate from LTA₄ and are of two types: (1) those containing asulfido-peptide side chain (LTC₄, LTD₄, and LTE₄), and (2) those thatare nonpeptidic (LTB₄). Leukotrienes comprise a group of naturallyoccurring substances that have the potential to contribute significantlyto the pathogenesis of a variety of inflammatory and ischemic disorders.The pathophysiological role of leukotrienes has been the focus of recentintensive studies.

As summarized by Lefer, A. M., Biochemical Pharmacology, 35, 2, 123-127(1986), both the peptide and non-peptide leukotrienes exertmicrocirculatory actions, promoting leakage of fluid across thecapillary endothelial membrane in most types of vascular beds. LTB₄ haspotent chemotactic actions and contributes to the recruitment andadherence of mobile scavenger cells to the endothelial membrane. LTC₄,LTD₄ and LTE₄ stimulate a variety of types of muscles. LTC₄ and LTD₄ arepotent bronchoconstrictors and effective stimulators of vascular smoothmuscle. This vasoconstrictor effect has been shown to occur inpulmonary, coronary, cerebral, renal, and mesenteric vasculatures.

Leukotrienes have been implicated in a number of pulmonary diseases.Leukotrienes are known to be potent bronchoconstrictors in humans. LTC₄and LTD₄ have been shown to be potent and selective peripheral airwayagonists, being more active than histamine. [See Drazen, J. M. et al.,Proc. Nat'l. Acad. Sci. USA, 77, 7, 4354-4358 (1980)]. LTC₄ and LTD₄have been shown in increase the release of mucus from human airways invitro. [See Marom, Z. et al., Am. Rev. Respir. Dis., 126, 449-451(1982).] The leukotriene antagonists of the present invention can beuseful in the treatment of allergic or non-allergic bronchial asthma orpulmonary anaphylaxis.

The presence of leukotrienes in the sputum of patients having cysticfibrosis, chronic bronchitis, and bronchiectasis at levels likely tohave pathophysiological effects has been demonstrated by Zakrzewski etal. [See Zakrzewski, J. T. et al., Prostaglandins, 28, 5, 641 (1984).]Treatment of these disease constitutes additional possible utility forleukotriene antagonists.

Leukotrienes have been identified in the nasal secretions of theallergic subjects who underwent in vivo challenge with specific antigen.The release of the leukotrienes was correlated with typical allergicsigns and symptoms. [See Creticos, P. S. et al., New England J. of Med.,310, 25, 1626-1629 (1984).] This suggests that allergic rhinitis isanother area of utility for leukotriene antagonists.

The role of leukotrienes and the specificity and selectivity of aparticular leukotriene antagonist in an animal model of the adultrespiratory distress syndrome was investigated by Snapper et al. [SeeSnapper, J. R. et al., Abstracts of Int'l Conf. on Prostaglandins andRelated Comp., Florence, Italy, p. 495 (Jun. 1986).] Elevatedconcentrations of LTD₄ were shown in pulmonary edema fluid of patientswith adult respiratory distress syndrome. [See Matthay, M. et al. J.Clin. Immunol., 4, 479-483 (1984).] Markedly elevated leukotriene levelshave been shown in the edema fluid of a patient with pulmonary edemaafter cardiopulmonary bypass. [See Swerdlow, B. N., et al., Anesth.Analg., 65, 306-308, (1986).] LTC and LTD have also been shown to have adirect systemic arterial hypotensive effect and produce vasoconstrictionand increased vasopermeability. [See Drazen et al., ibid.] This suggestsleukotriene antagonists can also be useful in the areas of adultrespiratory distress syndrome, pulmonary edema, and hypertension.

Leukotrienes have also been directly or indirectly implicated in avariety of non-pulmonary diseases in the ocular, dermatologic,cardiovascular, renal, trauma, inflammatory, carcinogenic and otherareas.

Further evidence of leukotrienes as mediators of allergic reactions isprovided by the identification of leukotrienes in tear fluids fromsubjects following a conjunctival provocation test and in skin blisterfluids after allergen challenge in allergic skin diseases andconjunctival mucosa. [See Bisgaard, H., et al., Allergy, 40, 417-423(1985).] Leukotriene immunoreactivity has also been shown to be presentin the aqueous humor of human patients with and without uveitis. Theconcentrations of leukotrienes were sufficiently high that thesemediators were expected to contribute in a meaningful way of tissueresponses. [See Parker, J. A. et al., Arch Opthalmol, 104, 722-724(1986).] It has also been demonstrated that psoriatic skin has elevatedlevels of leukotrienes. [See Ford-Hutchinson, J. Allergy Clin. Immunol.,74, 437-440 (1984).]. Local effects of intracutaneous injections ofsynthetic leukotrienes in human skin were demonstrated by Soter et al.[(See Soter et al., J. Clin Invest Dermatol, 80, 115-119 (1983).]Cutaneous vasodilation with edema formation and a neutrophil infiltratewere induced. Leukotriene synthesis inhibitors or leukotrieneantagonists can also be useful in the treatment of ocular anddermatological diseases such as allergic conjunctivitis, uveitis,allergic dermatitis or psoriasis.

Another area of utility for leukotriene antagonists is in the treatmentof cardiovascular diseases. Since peptide leukotrienes are potentcoronary vasoconstrictors, they are implicated in a variety of cardiacdisorders including arrhythmias, conduction blocks and cardiacdepression. Synthetic leukotrienes have been shown to be powerfulmyocardial depressants, their effects consisting of a decrease incontactile force and coronary flow. The cardiac effects of LTC₄ and LTD₄have been shown to be antagonized by a specific leukotriene antagonist,thus suggesting usefulness of leukotriene antagonists in the areas ofmyocardial depression and cardiac anaphylaxis. [See Burke, J. A. et al.,J. Pharmacology and Experimental Therapeutics, 221, 1, 235-241 (1982).]

LTC₄ and LTD₄ have been measured in the body fluids of rats in theendotoxic shock, but are rapidly cleared from the blood into the bile.Thus leukotrienes are formed in ischemia and shock. Specific inhibitorsof leukotriene biosynthesis reduce the level of leukotrienes andtherefore reduce manifestations of traumatic shock, endotoxic shock, andacute myocardial ischemia. Leukotriene receptor and antagonists havealso been shown to reduce manifestations of endotoxic shock and toreduce extension of infarct size. Administration of peptide leukotrieneshas been shown to produce significant ischemia or shock. [See Lefer, A.M., Biochemical Pharmacology, 35, 2, 123-127 (1986).] Thus further areasof utility for leukotriene antagonists can be the treatment ofmyocardial ischemia, acute myocardial infarction, salvage of ischemicmyocardium, angina, cardiac arrhythmias, shock and atherosclerosis.

Leukotriene antagonists can also be useful in the area of renal ischemiaor renal failure. Badr et al. have shown that LTC₄ produces significantelevation of mean arterial pressure and reductions in cardiac output andrenal blood flow, and that such effects can be abolished by a specificleukotriene antagonist. [See Badr, K. F. et al., Circulation Research,54, 5, 492-499 (1984).] Leukotrienes have also been shown to have a rolein endotoxin-induced renal failure and the effects of the leukotrienesselectively antagonized in this model of renal injury. [See Badr, K. F.et al., Kidney International, 30, 474-480 (1986).] LTD₄ has been shownto produce local glomerular constrictor actions which are prevented bytreatment with a leukotriene antagonist. [See Badr, K. F. et al., KidneyInternational, 29, 1, 328 (1986).] LTC₄ has been demonstrated tocontract rat glomerular mesangial cells in culture and thereby effectintraglomerular actions to reduce filtration surface area. [See Dunn. M.J. et al., Kidney International, 27, 1, 256 (1985).] Thus another areaof utility for leukotriene antagonists can be in the treatment ofglomerulonephritis.

Leukotrienes have also been indicated in the area of transplantrejection. An increase in cardiac and renal allograft survival in thepresence of a leukotriene receptor antagonist was documented by Foegh etal. [See Foegh, M. L. et al. Advances in Prostaglandin, Thromboxane, andLeukotriene Research, 13, 209-217 (1985).] Rejection of rat renalallografts was shown to produce increased amounts of LTC₄. [See Coffman,T. M. et al., Kidney International, 29, 1, 332 (1986).]

A further area of utility for leukotriene antagonists can be intreatment of tissue trauma, burns, or fractures. A significant increasein the production of cysteinyl leukotrienes was shown after mechanicalor thermal trauma sufficient to induce tissue edema and circulatory andrespiratory dysfunction. [See Denzlinger, C. et al., Science, 230,330-332 (1985).]

Leukotrienes have also been shown to have a role in acute inflammatoryactions. LTC₄ and LTD₄ have potent effects on vascular caliber andpermeability and LTB₄ increases leukocyte adhesion to the endothelium.The arteriolar constriction, plasma leakage, and leukocyte adhesion bearclose resemblance to the early events in acute inflammatory reactions.[See Dahlen, S. E. et al., Proc. Natl. Acad. Sci. USA, 78, 6, 3887-3891(1981).] Mediation of local homeostasis and inflammation by leukotrienesand other mast cell-dependent compounds was also investigated by Lewiset al. [See Lewis, R. A. et al., Nature, 293, 103-108 (1981).]Leukotriene antagonists can therefore be useful in the treatment ofinflammatory diseases including rheumatoid arthritis and gout.

Cysteinyl leukotrienes have also been shown to undergo enterohepaticcirculation, and thus are indicated in the area of inflammatory liverdisease. [See Denzlinger, C. et al., Prostaglandins Leukotrienes andMedicine, 21, 321-322 (1986).] Leukotrienes can also be importantmediators of inflammation in inflammatory bowel disease. [See Peskar, B.M. et al., Agents and Actions, 18, 381-383 (1986). Leukotrieneantagonists thus can be useful in the treatment of inflammatory liverand bowel disease.

Leukotrienes have been shown to modulate IL-1 production of humanmonocytes. [See Rola-Pleszczynski, M. et al., J. of Immun., 135, 6,3958-3961 (1985).] This suggests that leukotriene antagonists may play arole in IL-1 mediated functions of monocytes in inflammation and immunereactions.

LTA₄ has been shown to be a factor in inducing carcinogenic tumors andis considered a link between acute immunologic defense reactions andcarcinogenesis. Leukotriene antagonists can therefore possibly haveutility in treatment of some types of carcinogenic tumors. [SeeWischnewsky, G. G. et al. Anticancer Res. 5, 6, 639 (1985).]

Leukotrienes have been implicated in gastric cytodestruction and gastriculcers. Damage of gastrointestinal mucosa because of potentvasoconstriction and stasis of blood flow is correlated with increasedlevels of LTC₄. Functional antagonism of leukotriene effects mayrepresent an alternative in treatment of mucosal injury. [See Dreyling,K. W. et al., British J. Pharmacology, 88, 236P (1986), and Peskar, B.M. et al. Prostaglandins, 31, 2, 283-293 (1986).] A leukotrieneantagonist has been shown to protect against stress-induced gastriculcers in rats. [See Ogle, C. W. et al., IRCS Med. Sci., 14, 114-115(1986).]

Other areas in which leukotriene antagonists can have utility becauseleukotrienes are indicated as mediators include prevention of prematurelabor [See Clayton, J. K. et al., Proceedings of the BPS, 573P, 17-19Dec. 1984]; treatment of migraine headaches [See Gazzaniga, P. P. etal., Abstracts Int'l Conf. on Prostaglandins and Related Comp., 121,Florence, Italy (Jun. 1986)]; and treatment of gallstones [See Doty, J.E. et al., Amer. J. of Surgery, 145, 54-61 (1983) and Marom, Z. et al.,Amer. Rev. Respir. Dis., 126, 449-451 (1982).]

By antagonizing the effects of LTC₄, LTD₄ and LTE₄ or otherpharmacologically active mediators at the end organ, for example, airwaysmooth muscle, the compounds and pharmaceutical compositions of theinstant invention are valuable in the treatment of diseases in subjects,including human or animals, in which leukotrienes are a key factor.

SUMMARY OF THE INVENTION

This invention relates to compounds represented by structural formula(I) ##STR2## wherein q is 0, 1, or 2;

R₁ is (L)_(a) --(CH₂)_(b) --(T)_(c) --B

a is 0 or 1;

b is 3 to 14;

c is 0 or 1;

L and T are independently sulfur, oxygen, or CH₂ with the proviso that Tand L are not sulfur when q is 1 or 2; and

B is C₁₋₄ alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl,thienyl, cyclohexyl or phenyl optionally monosubstituted with Br, Cl,CF₃, C₁₋₄ alkoxy, C₁₋₄ alkyl, methylthio, or trifluoromethylthio;

R₂ and A are independently selected from H, CF₃, C₁₋₄ alkyl, C₁₋₄alkoxy, F, Cl, Br, I, OH, NO₂ or NH₂ ;

or R₁ and A are H and

R₂ is (L)_(a) --(CH₂)_(b) --(T)_(c) --B wherein a, b, c, L, T, and B areas defined above;

Y is COR₃ or ##STR3## wherein R₃ is OH, NH₂, aryloxy, or C₁₋₆ alkoxy;

n is 0 or 1;

p is 0, 1 or 2;

X is H, OH, C₁₋₄ alkoxy, or F; and

Z is COR₃, or tetrazolyl; ##STR4## m is 0 to 6 R₄ and R₅ areindependently hydrogen or C₁₋₄ alkyl at any position when m is not 0;

W is a 5-membered heteroaryl ring selected from tetrazole, thiazole,triazole, thiophene, furan, oxazole, thiadiazole, pyrrole, or pyrazole,each group unsubstituted or substituted with one to three ##STR5## R₄and R₅ are as defined above, j is 0 to 6, and

V is hydrogen, C₁₋₄ alkyl, COR₃, SO₃ H, SO₂ H, SO₂ NH₂, COCH₂ OH,CHOHCH₂ OH, or tetrazolyl with R₃ as defined above;

or a pharmaceutically acceptable salt thereof.

This invention further relates to the ester or diester derivatives ofthe compounds of Formula (I).

This invention includes all stereoisomers, racemates, or mixturesthereof. For example, W can be 1,2,3-triazole, 1,3,4-triazole;1,2,3-thiadiazole, 1,3,4-thiadiazole, and other possible steroisomers.

This invention further relates to pharmaceutical compositions comprisinga pharmaceutical carrier or diluent and a nontoxic amount of thecompound of formula (I). Such compositions are useful for inhibiting theeffects of leukotrienes and in treating diseases in which leukotrienesare a factor.

This invention further relates to pharmaceutical compositions comprisinga pharmaceutical carrier or diluent and nontoxic amounts of a compoundof formula (I) and a histamine H₁ -receptor antagonist. Suchcompositions are useful in inhibiting antigen-induced respiratoryanaphylaxis.

This invention further relates to methods for inhibiting the effects ofleukotrienes. This invention also relates to methods for inhibitingantigen-induced respiratory anaphylaxis comprising administration of aneffective amount of the above-described pharmaceutical compositions.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are represented by the following generalstructural formula (I) ##STR6## wherein q is 0, 1, or 2;

R₁ is (L)_(a) --(CH₂)_(b) --(T)_(c) --B;

a is 0 or 1;

b is 3 to 14;

c is 0 or 1;

L and T are independently oxygen, sulfur, or CH₂ with the proviso that Land T are not sulfur when q is 1 or 2; and

B is C₁₋₄ alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl,thienyl, cyclohexyl, or phenyl optionally monosubstituted with Br, Cl,CF₃, C₁₋₄ alkoxy, C₁₋₄ alkyl, methylthio, or trifluoromethylthio;

R₂ and A are independently selected from H, CF₃, C₁₋₄ alkyl, C₁₋₄alkoxy, F, Cl, Br, I, OH, NO₂ or NH₂ ;

or R₁ and A are H and

R₂ is (L)_(a) --(CH₂)_(b) --(T)_(c) --B wherein a, b, c, L, T, and B areas defined above;

Y is COR₃ or ##STR7## wherein R₃ is OH, NH₂, aryloxy or C₁₋₆ alkoxy;

n is 0 or 1;

p is 0, 1, or 2;

X is H, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy or F; and

Z is COR₃, or tetrazolyl; ##STR8## m is 0 to 6 R₄ and R₅ areindependently hydrogen or C₁₋₄ alkyl at any position when m is not 0;and

W is a 5-membered ring heteroaryl group selected from tetrazole,thiazole, triazole, thiophene, furan, oxazole, thiadiazole, pyrrole,imidazole, or pyrazole, each group unsubstituted or substituted with oneto three ##STR9## wherein R₄ and R₅ are as defined above,

j is 0 to 6; and

V is hydrogen, C₁₋₄ alkyl, COR₃, SO₃ H, SO₂ H, SO₂ NH₂, COCH₂ OH,CHOHCH₂ OH, or tetrazolyl, with R₃ as defined above;

or a pharmaceutically acceptable salt thereof.

This invention includes all stereoisomers, racemates, or mixturesthereof. For example, W can be 1,2,3-triazole; 1,3,4-triazole;1,2,3-thiadiazole, 1,3,4-thiadiazole, and other possible steroisomers.

The compounds of this invention further comprise the ester and diesterderivatives of the compounds of Formula (I).

A subgeneric class of these compounds are those represented bystructural formula (I) where Y is CO₂ H. Particular members of thissubgeneric class are exemplified by the following compounds:

(1) 2-(2-Dodecylphenyl)-2-[(1-carboxymethyl-5-tetrazolyl]thio]aceticacid;

(2) 2-(2-Dodecylphenyl)-2-[[1-(3-carboxymethyl-5-tetrazolyl]thio]aceticacid;

(3) 2-(2-Dodecylphenyl)-2-[(1-sulfomethyl-5-tetrazolyl) thio]aceticacid;

(4) 2-(2-Dodecylphenyl)-2-[(1-methyl-5-tetrazolyl) thio]acetic acid;

(5)2-[2-(8-Phenylocytyl)phenyl]-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]aceticacid;

(6) 2-[2-(Tetrazol-5-yl)ethylthio]-2-(2-dodecylphenyl)acetic acid; and

(7) 2-(2-Dodecylphenyl)-2-(5-carboxy-4-methyl-2-thiazolylthio)aceticacid;

A second subgeneric class of these compounds are those represented bystructural formula (I) where Y is CH₂ COOH. Particular members of thissubgeneric class are exemplified by the following compounds:

(1) 3-(2-Dodecylphenyl)-3-[[1-(3-carboxypropyl)-5-tetrazolyl]propanoicacid;

(2)3-[2-(8-Phenyloctyl)phenyl]-3-[(1-carboxymethyl-5-tetrazolyl)thio]propanoicacid; and

(3)3-[2-(8-Phenyloctyl)phenyl]-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]propanoicacid.

A third subgeneric class of these compounds are those represented bystructural formula (I) where Y is ##STR10## Particular members of thissubgeneric class are exemplified by the following compounds:

(1)3-[2-(8-phenylocytyl)phenyl]-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]-2-hydroxypropanoicacid; and

(2)3-[2-(8-phenylocytyl)phenyl]-3-[(1-carboxymethyl-5-tetrazolyl]thio]-2-hydroxypropanoicacid.

Some of the compounds of formula (I) contain one or two asymmetriccenters. This leads to the possibility of two or four stereoisomers foreach compound. The present invention includes all such stereoisomers,racemates, or mixtures thereof. The compounds of the present invention,depending upon this structure, are capable of forming salts with knownpharmaceutically acceptable bases, according to procedures well known inthe art. Such acceptable bases include inorganic and organic bases, suchas ammonia, arginine, organic amines, alkaline earth and alkali metalbases. Of particular utility are the dipotassium, magnesium, calcium,diammonium and disodium salts of the diacid compounds of formula (I).

The compounds of the formula (I) wherein Y is CO₂ H are convenientlyprepared by an aldehyde precursor of the following structural formula(II) ##STR11## wherein A, R₁ and R₂ are described above. A compound offormula (II) is treated with trimethylsilyl cyanide in the presence ofzinc iodide at low temperatures in an inert solvent to form thetrimethylsilyl-protected cyanohydrin. Treatment of this with gaseoushydrogen chloride in methanol provides the methyl 2-hydroxyacetatederivative which is converted to the 2-chloroacetate with thionylchloride. This valuable intermediate is then reacted with an appropriatethiol selected to give, after removal of ester protective groups, thedesired product of formula (I).

The compounds of the formula (I) where Y is CH(X)CO₂ H, wherein X is H,C₁₋₄ alkyl, or C₁₋₄ alkoxy, are prepared by reacting the appropriatealdehyde of the formula (II) and an esterified bromoacetate,conveniently t-butyl bromoacetate, with a mixture of diethyl aluminumchloride, zinc dust and a catalytic amount of cuprous bromide at lowtemperatures in an inert solvent to give the esterified3-hydroxy-propionate derivative which is reacted directly with asubstituted thiol in trifluoroacetic acid. Alternatively, a mixture oftrimethyl borate and zinc in tetrahydrofuran may be used to prepare the3-hydroxypropionate derivative. By employing an esterified2-bromo-propionate in the above reaction with an aldehyde (II), thecompounds of the formula (I) wherein Y is CH(CH₃)CO₂ H are obtained.

Alternatively, the compounds of the formula (I) wherein Y is CH(X)CO₂ Hwherein X is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, or fluoro are prepared from apropionate precursor of the following structural formula (IV) ##STR12##wherein, A, R₁ and R₂ are described above, R₁₀ is a conventional esterprotective group, such as t-butyl or C₁₋₄ alkyl, and R₁₁ is hydrogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, or fluoro. A compound of formula (IV) isreacted with a mixture of alkali metal alkoxide, such as sodiummethoxide, and an appropriate thiol to give, after removal of the esterprotective group, the desired product of formula (I).

The propionate precursors of formula (IV) are prepared from thecorresponding aldehydes of formula (II) by general procedures such asreaction with an alkyl (triphenylphosphoranylidene)acetate or byconversion of the aldehyde to a 3-hydroxypropionate derivative, asdescribed above, followed by an elimination reaction to form the doublebond. Additionally, the propionate precursor is obtained from a3-methanesulfonyloxypropionate derivative by treatment withtriethylamine.

The compounds of the formula (I) where Y is CH(OH)(CH₂)_(P) CO₂ H areprepared from an epoxide precursor of the following structural formula(V) ##STR13## wherein A, R₁ and R₂ are described above, p is 0, 1 or 2and R₁₂ is a conventional ester protective group, such as t-butyl orC₁₋₄ alkyl such as methyl or ethyl. A compound of formula (V) is reactedin an inert solvent with triethylamine and the appropriate thiolselected to give, after removal of ester protective groups, a desiredproduct of formula (I).

The epoxide precursors of formula (V) where p is 2 are prepared byreaction of the Grignard derivative of a bromobenzene compound of theformula (VI) ##STR14## with acrolein to give the corresponding enolderivative which is treated with a trialkylorthoacetate, followed byepoxidation using m-chloroperbenzoic acid.

The epoxide precursors of formula (V) where p is 1 can be prepared byArndt-Eistert homologation of the compound where p is 0 and R₁₂ is H.

The epoxide precursors of formula (V) where p is O are prepared byreaction of an aldehyde of the formula (II) with a lower alkylchloroacetate and an alkali metal alkoxide, such as sodium methoxide inan appropriate solvent such as diethyl ester or methylene chloride.

The compounds of the formula (I) wherein Y is (CH₂)₃ CO₂ H are preparedfrom a tetrahydro-4H-pyran-2-one precursor of the following structuralformula (VII) ##STR15## wherein A, R₁ and R₂ are described above. Acompound of formula (VII) is reacted with a mixture of zinc iodide and asubstituted thiol in an inert solvent or with a substituted thiol intrifluoroacetic acid to give, after removal of any ester protectivegroup, a product of formula (I).

The tetrahydro-4H-pyran-2-one precursors of formula (VII) are preparedby reaction of the Grignard derivative of the bromobenzene compound offormula (VI) with chlorotitanium triisopropoxide followed by reactionwith 5-oxovalerate alkyl ester.

The aldehydes of the formula (II) are known or readily preparedutilizing the general procedures described as follows.

The aldehyde precursors to the compounds of the formula (I) wherein R₁is, for example, an alkyl radical containing 8 to 13 carbon atoms areprepared from the appropriate 2-alkylphenyl-4-,4-dimethyloxazoline [seeMeyers et al. J. Org. Chem., 43 1372 (1978)].

The aldehyde precursors of the compounds of the formula (I) wherein R₁is, for example, an alkoxy radical containing 7 to 12 carbon atoms areprepared by the O-alkylation of the appropriate 2-hydroxybenzaldehydewith the corresponding alkylating agent by standard methods.

The thioalkyl containing aldehyde precursors of the compounds of theformula (I) are prepared by the reaction of the appropriatelysubstituted o-haloalkylthiobenzene (for example, a compound of formula(III): ##STR16## wherein X is halo and R is alkyl, with magnesium anddimethylformamide by standard methods.

The phenylthioalkyl containing aldehyde precursors of the compounds ofthe formula (I) are prepared by the reaction of the appropriatelysubstituted haloalkylbenzaldehyde with a thiophenol and triethylamine.

The heteroaryl mercaptan precursors necessary to prepare the compoundsof formula (I) are known compounds and are conveniently preparedemploying standard chemical reactions. The mercapto derivatives of theseprecursors are prepared according to known methods. For example,5-(2-mercaptoethyl)tetrazole can be prepared by addingβ-merceptopropionitrile to a mixture of sodium azide and aluminiumchloride in tetrahydrofuran. The preparation of tetrazolthiol compoundswith various substituents is described in U.S. Pat. Nos. 4,048,311,4,220,644; and 4,286,089 of Berges. The preparation of thiazolthiols andthiadiazolthiols with various substituents is taught in U.S. Pat. Nos.3,868,369 and 3,989,694 of Berges. These mercaptans are reacted asdescribed above to yield compounds of formula (I).

Appropriate modifications of the general processes disclosed, and asfurther described in the Examples provided hereinbelow, furnish thevarious compounds defined by formula (I).

The leukotriene antagonist activity of the compounds of this inventionis measured by the ability of the compounds to inhibit the leukotrieneinduced contraction of guinea pig tracheal tissues in vitro. Thefollowing methodology was employed: In vitro: Guinea pig (adult malealbino Hartley strain) tracheal spiral strips of approximate dimensions2 to 3 mm cross-sectional width an 3.5 cm length were bathed in modifiedKrebs buffer in jacketed 10 ml tissue bath and continuously aerated with95% O₂ /5% CO₂. The tissues were connected via silk suture to forcedisplacement transducers for recording isometric tension. The tissueswere equilibrated for 1 hr., pretreated for 15 minutes with meclofenamicacid (1 M) to remove intrinsic prostaglandin responses, and thenpretreated for an additional 30 minutes with either the test compound orvehicle control. A cumulative concentration-response curve for LTD₄ ontriplicate tissues were generated by successive increases in the bathconcentration of the LTD₄. In order to minimize intertissue variabilityas a percentage of the maximum response obtained to a reference agonist,carbachol (10 M).

Calculations: The averages of the triplicate LTD₄ concentration-responsecurves both in the presence and absence of the test compound wereplotted on log graph paper. The concentration of LTD₄ needed to elicit30% of the contraction elicited by carbachol was measured and defined asthe EC₃₀. The -log K_(B) value for the test compound was determined bythe following equations: ##EQU1##

The compounds of this invention possess biosignificant antagonistactivity against leukotrienes. The antagonist activity of representativecompounds of this invention is tabulated below in Table I (other dataappears in the preparative examples). The -log K_(B) values werecalculated from the above test protocol. Where compounds were testedmore than once, the -log K_(B) values given herein represent the currentaverage data.

                  TABLE I                                                         ______________________________________                                        Leukotriene Antagonist Activity                                                                                In                                                                            Vitro                                        Compounds of Formula (I)*        -Log                                         W     m     (C);R.sub.4 R.sub.5 V                                                                     R.sub.1                                                                              Y         K.sub.8                              ______________________________________                                        5-tetra-                                                                            0     1-CH.sub.2 COOH                                                                           C.sub.12 H.sub.25                                                                    CO.sub.2 H                                                                              6.1                                  zolyl                                                                         5-tetra-                                                                            0     1-CH.sub.2 SO.sub.3 H                                                                     C.sub.12 H.sub.25                                                                    CO.sub.2 H                                                                              6.4                                  zolyl                                                                         5-tetra-                                                                            0     1-CH.sub.3  C.sub.12 H.sub.25                                                                    CO.sub.2 H                                                                              5.8                                  zolyl                                                                         5-tetra-                                                                            0     1-(CH.sub.2).sub.3 COOH                                                                   C.sub.12 H.sub.25                                                                    CO.sub.2 H                                                                              7.4                                  zolyl                                                                         5-tetra-                                                                            0     1-(CH.sub.2).sub.3 COOH                                                                   (CH.sub.2).sub.8 Ph                                                                  CO.sub.2 H                                                                              6.0                                  zolyl                                                                         5-tetra-                                                                            0     1-(CH.sub.2).sub.3 COOH                                                                   C.sub.12 H.sub.25                                                                    CH.sub.2 CO.sub.2 H                                                                     6.6                                  zolyl                                                                         5-tetra-                                                                            0     1-CH.sub.2 COOH                                                                           (CH.sub.2).sub.8 Ph                                                                  CH.sub.2 CO.sub.2 H                                                                     6.3                                  zolyl                                                                         5-tetra-                                                                            0     1-(CH.sub.2).sub.3 COOH                                                                   (CH.sub.2).sub.8 Ph                                                                  CH.sub.2 CO.sub.2 H                                                                     6.0                                  zolyl                                                                         5-tetra-                                                                            2     1-H         C.sub.12 H.sub.25                                                                    CO.sub.2 H                                                                              6.5                                  zolyl                                                                         5-tetra-                                                                            0     1-(CH.sub.2).sub.3 COOH                                                                   (CH.sub.2).sub.8 Ph                                                                  CH(OH)CO.sub.2 H                                                                        7.0                                  zolyl                                                                         5-tetra-                                                                            0     1-CH.sub.2 COOH                                                                           (CH.sub.2).sub.8 Ph                                                                  CH(OH)CO.sub.2 H                                                                        7.0                                  zolyl                                                                         2-thia-                                                                             0     4-CH.sub.3,5-COOH                                                                         C.sub.12 H.sub.15                                                                    COOH      6.7                                  zolyl                                                                         ______________________________________                                         ##STR17##                                                                     ##STR18##                                                                     R.sub.4 and R.sub.5 are H, W is optionally substituted with (C);R.sub.4       R.sub.5V; R.sub.2 and A are H; and q is 0.                               

Pharmaceutical compositions of the present invention comprise apharmaceutical carrier or diluent and an amount of a compound of theformula (I) or a pharmaceutically acceptable salt, such as an alkalimetal salt thereof, sufficient to produce the inhibition of the effectsof leukotrienes, such as symptoms of asthma and other hypersensitivitydiseases.

When the pharmaceutical composition is employed in the form of asolution or suspension, examples of appropriate pharmaceutical carriersor diluents include: for aqueous systems, water; for non-aqueoussystems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil,peanut oil, sesame oil, liquid paraffins and mixtures thereof withwater; for solid systems, lactose, kaolin and mannitol, and for aerosolsystems, dichlorodifluoromethane, chlorotrifluoroethane and compressedcarbon dioxide propellants. Also, in addition to the pharmaceuticalcarrier or diluent, the instant compositions may include otheringredients such as stabilizers, antioxidants, preservatives,lubricants, suspending agents, viscosity modifiers and the like,provided that the additional ingredients do not have a detrimentaleffect on the therapeutic action of the instant compositions.

The nature of the composition and the pharmaceutical carrier or diluentwill, of course, depend upon the intended route of administration, i.e.parenterally, topically, orally or by inhalation.

In general, particularly for the prophylactic treatment of asthma, thecompositions will be in a form suitable for administration byinhalation. Thus the compositions will comprise a suspension or solutionof the active ingredient in water for administration by means of aconventional nebulizer. Alternatively the compositions will comprise asuspension or solution of the active ingredient in a conventionalliquified propellant or compressed gas to be administered from apressurized aerosol container. The compositions may also comprise thesolid active ingredient diluted with a solid diluent for administrationfrom a powder inhalation device. In the above compositions, the amountof carrier or diluent will vary but preferably will be the majorproportion of a suspension or solution of the active ingredient. Whenthe diluent is a solid it may be present in lesser, equal or greateramounts than the solid active ingredient.

For parenteral administration the pharmaceutical composition will be inthe form of a sterile injectable liquid such as an ampule or an aqueousor nonaqueous liquid suspension.

For topical administration the pharmaceutical composition will be in theform of a cream or ointment.

Usually a compound of formula I is administered to an animal subject,including humans, in a composition comprising a nontoxic amountsufficient to produce an inhibition of the symptoms of an allergicresponse. When employed in this manner, the dosage of the composition iseasily determined by those skilled int eh art and are generally selectedfrom the range of from 350 mg. to 700 mg. of active ingredient for eachadministration. For convenience, equal doses will be administered 1 to 4times daily with the daily dosage regimen being selected from about 350mg. to about 2800 mg.

The pharmaceutical preparations thus described are made following theconventional techniques of the pharmaceutical chemist as appropriate tothe desired end product.

Included within the scope of this disclosure is the method of inhibitingthe symptoms of an allergic response which comprises administering to ananimal subject a therapeutically effective amount for producing saidinhibition of a compound of formula I, preferably in the form of apharmaceutical composition. The administration may be carried out indosage units at suitable intervals or in single doses as needed. Usuallythis method will be practiced when relief of allergic symptoms isspecifically required. However, the method is also usefully carried outas continuous or prophylactic treatment. It is within the skill of theart to determine by routine experimentation the effective dosage to beadministered from the dose range set forth above, taking intoconsideration such factors as the degree of severity of the allergiccondition being treated, and so forth.

Compounds of this invention, alone and in combination with a histamineH₁ -receptor antagonist, inhibit antigen induced contraction ofisolated, sensitized guinea pig trachea (a model of respiratoryanaphylaxis).

Pharmaceutical compositions, as described hereinabove, of the presentinvention also comprise a pharmaceutical carrier or diluent and acombination of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof, and a histamine H₁ -receptor antagonist inamounts sufficient to inhibit antigen-induced respiratory anaphylaxis.Examples of histamine H₁ -receptor antagonists include mepyramine,2-[4-(5-bromo-3-methyl-pyrid-2yl)butylamino]-5-[(6-methyl-pyrid-3-yl)methyl]-4-pyrimidone and other known H₁ -receptor antagonists. Theabove-defined dosage of a compound of formula I is conveniently employedfor this purpose with the known effective dosage for the histamine H₁-receptor antagonist. The methods of administration described above forthe single active ingredient can similarly be employed for thecombination with a histamine H₁ -receptor antagonist.

The following examples illustrate the preparation of the compounds ofthis invention and their incorporation into pharmaceutical compositionsand as such are not to be considered as limiting the invention set forthin the claims appended hereto.

EXAMPLE 1 Preparation of2-(2-Dodecylphenyl)-2[(1-methyl-5-tetrazolyl)thio]acetic acid (a)2-(2-Dodecylphenyl)-4,4-dimethyloxazoline

To freshly prepared dodecylmagnesium bromide (from 30.13 mmol of dodecylbromide and 26.20 mmol of magnesium) in distilled tetrahydrofuran (50ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline [A. I. Meyers etal., J. Org. Chem., 43, 1372 (1978)] (17.88 mmol) in tetrahydrofuran (30ml). The resultant yellow solution was stirred under argon at ambienttemperature for 20 hours. The solution was cooled in an ice water bathand quenched with aqueous ammonium chloride (100 ml). The reactionproduct was extracted into diethyl ether (100 ml) and the organic phasewas washed with saturated sodium chloride solution (50 ml) and thendried over anhydrous magnesium sulfate. Evaporation of the organic phaseafforded a colorless oil which was purified by flash chromatography oversilica gel with 5 percent ethyl acetate in hexane as eluant to afford todesired product as a pale yellow oil.

Analysis for C₂₃ H₃₇ NO: Calculated: C, 80.41; H, 10.85; N, 4.08. Found:C, 80.22; H, 10.56; N, 3.87.

(b) 2-(2-Dodecylphenyl)-3,4,4-trimethyloxazolinium iodide

A solution of the compound of Example 1(a) (17.2 mmol) in methyl iodide(20 ml) was refluxed under argon for 18 hours. The volatiles wereremoved under vacuum and the solid residue triturated with ethyl acetate(25 ml) to afford the desired product as white crystals (mp 78°-84° C.).

(c) 2-Dodecylbenzaldehyde

To an ice cold solution of the compound of Example 1(b) (10.0 mmol) inmethanol (50 ml) over a period of 15 minutes was added in small portionssodium borohydride (10.0 mmol). The reaction mixture was allowed to stirfor 30 minutes and was then quenched with 5 percent sodium hydroxide (50ml). The reaction mixture was extracted with diethyl ether (2×50 ml) andthe extract was washed with brine (50 ml) and dried over anhydrousmagnesium sulfate. Evaporation of the extract afforded an oil which wasdissolved in acetone (50 ml) and 3N hydrochloric acid (10 ml) was added.The mixture was flushed with argon and stirred for 16 hours at ambienttemperature. The volatiles were removed under vacuum and the residuepartitioned between diethyl ether (50 ml) and water (50 ml). The aqueousphase was extracted with more diethyl ether (50 ml). The combinedorganic phase was washed with brine (50 ml) and dried over anhydrousmagnesium sulfate. Evaporation of the organic phase yielded an oil whichwas purified by flash chromatography over silica gel with 2 percentethyl acetate in hexane as eluant to afford the desired product as acolorless oil.

Analysis for C₁₉ H₃₀ O: Calculated: C, 83.15; H, 11.02. Found C, 82.59;H, 10.65.

(d) Methyl 2-(2-dodecylphenyl)-2-hydroxyacetate

The compound of Example 1(c) (17.2 mmol) was dissolved in the methylenechloride (20 ml) and stirred at 0° C. under argon. Zinc iodide (1.87mmol) was added, followed by the dropwise addition of trimethylsilylcyanide (2.45 ml, 18.3 mmoles) dissolved in methylene chloride (30 ml).After 1 hour at 0° C. the ice bath was removed and the mixture stirredfor 1 hour at room temperature. The solvent was stripped and methanol(100 ml) was added after the residue was cooled in an ice bath. Excesshydrogen chloride was bubbled into the solution while the mixture wasstirred at ice bath temperature. The ice bath was then removed and themixture stirred at room temperature for 18 hours. Water (20 ml) wasadded and the mixture stirred for 2 hours. The solvent was evaporatedand the aqueous residue extracted with ethyl acetate. The combinedorganic phases were dried over anhydrous sodium sulfate, filtered andevaporated. The crude product was flash chromatographed on silica gel,eluted with 20% ethyl acetate/hexane, to give the product as a clearcolorless liquid.

(e) Methyl 2-Chloro-2-(2-dodecylphenyl)acetate

The compound of Example 1(d) (12 mmol) was stirred under argon in an icebath and thionyl chloride (20 ml) was added in a single portion. The icebath was removed and the mixture was stirred under argon for 18 hours.The solvent was stripped and the residue was flash chromatographed on200 grams of silica gel with 20% methylene chloride/carbon tetrachlorideas eluant to give the product as a clear colorless liquid.

(f) Methyl 2-(2-Dodecylphenyl)-2-[(1-methyl-5-tetrazolyl) thio]acetate

The compound of Example 1(e) was mixed in an amount of 0.7 g (0.002 mol)with 0.37 g (0.0027 mol) of 5-mercapto-1-methyltetrazole sodium salt, 1ml of triethylamine and 20 ml of methylene chloride. The mixture wasstirred at ambient temperature under argon for 3 days. The reactionmixture was washed with water, dried over anhydrous magnesium sulfateand filtered. The filtrate was concentrated under vacuum to yield 0.7 gof product.

(g) 2-(2-Dodecylphenyl)-2-[(1-methyl-5-tetrazolyl) thio]acetic acid

The compound of Example 1(f) in an amount of 0.7 g (0.0016 mol) wasdissolved in 5 ml of methanol, mixed with 0.4 g (0.01 mol) of sodiumhydroxide, and stirred for 2 hours. The reaction mixture wasconcentrated under vacuum and the residual oil was redissolved in 5 ml.of water. The pH of the solution was adjusted to 4.8 or until aprecipitate formed. The precipitate was filtered, redissolved inmethylene chloride, washed with water, dried over anhydrous magnesiumsulfate, filtered, and concentrated under vacuum. The resulting 0.3 g ofoil was flash chromatographed on silica gel, with methylene chloride,0.005% methanol, and 0.001% formic acid as eluent to yield 0.18 g of oilwhich solidified to a low melting wax.

Similarly, the following compounds are prepared according to the generalmethod of Example 1 from the 2-(2-methoxyphenyl)-4,4-dimethyloxazolineand the appropriate alkyl halide:

2-(2-Tetradecylphenyl)-2-[(1-methyl-5-tetrazolyl)thio]acetic acid; and

2-(2-Octylphenyl)-2-[(1-methyl-5-tetrazolyl)thio]acetic acid.

EXAMPLE 2 Preparation of2(2-Dodecylphenyl)-2[(1-carboxymethyl-5-tetrazolyl)thio]acetic acid. (a)Methyl2-(2-Dodecylphenyl)-2[(1-carbethoxymethyl-5-tetrazolyl)thio]acetate

The compound of Example 1(e) (352 mg, 1 mmol), triethylamine (0.21 ml,1.5 mmol) and 5-mercapto-1-carbethoxymethyltetrazole (250 mg, 1.33 mmol)were combined in 25 ml of methylene chloride. The mixture was stirredunder argon at ambient temperature for 2 days. The solvent was strippedand the residue flash chromatographed on 50 grams of silica gel elutedwith 15% ethyl acetate/hexane to give the product (500 mg, 99%) as aclear colorless liquid.

(b) 2-(2-Dodecylphenyl)-2-[2-(1-carboxymethyl-5-tetrazolyl)thio]aceticacid

The compound of Example 2(a) (260 mg, 0.52 mmol) was dissolved in 4.2 mlof methanol and stirred under argon in an ice bath. An 1N solution ofsodium hydroxide (2.1 ml, 2.1 mmol) was added. The ice bath was removed,and the mixture stirred for 1 hour at ambient temperature during whichtime a white precipitate formed. The methanol was evaporated and anadditional 4 ml of water added to give a slightly turbid mixture whichwas stirred overnight at ambient temperature. The mixture was acidifiedwith dilute hydrochloric acid, extracted with ethyl acetate, dried overanhydrous sodium sulfate, filtered and evaporated. The crude product wasrecrystallized from ethyl acetate/hexane to yield the desired product(204 mg, 86%) as a white crystalline solid with m.p. 147°-148° C.

Analysis for C₂₃ H₃₄ N₄ O₄ S-- Calculated: C,59.72; H,7.41; N,12.11.Found: C,59.61; H,7.27; N,12.15.

EXAMPLE 3 Preparation of2-(2-Dodecylphenyl)-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]aceticacid (a) Methyl2-(2-dodecylphenyl)-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]acetate

The compound of Example 1(e) (325 mg, 1 mmol), triethylamine (0.42 ml, 3mmol), 5-mercapto-1-(3-carboxypropyl)tetrazole (250 mg, 1.33 mmol) and25 ml of methylene chloride were combined and stirred under argon atambient temperature overnight. The solvent was stripped and the residueflash chromatographed on 50 grams of silica gel, eluted with 70:30:1(hexane: ethyl acetate: formic acid) to yield the desired product (411mg, 82%).

(b) 2-(2-Dodecylphenyl)-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]aceticacid

The compound of Example 3(a) (411 mg, 0.82 mmol) was dissolved in 10 mlof methanol and stirred under argon in an ice bath. A 1N solution ofsodium hydroxide (3.2 ml, 3.2 mmol) was added dropwise, the ice bathremoved and the mixture stirred overnight at ambient temperature. Thesolvent was stripped and the residue acidified with dilute hydrochloricacid at ice bath temperature. The crude product was extracted with ethylacetate, dried over anhydrous sodium sulfate, filtered and evaporated.The residue was flash chromatographed on 50 grams of silica gel elutedwith 30:70:1 (ethyl acetate: hexane:formic acid) followed by 50:50:1(ethyl acetate:hexane:formic acid). Recrystallization from ethylether/hexane gave the desired product (285 mg, 71%) as a whitecrystalline solid with m.p. 86°-88° C.

Analysis for C₂₅ H₃₈ N₄ O₄ S-- Calculated: C, 61,20; H,7.81; N,11.42;S,6.53. Found: C,61.43; H,7.83; N,11.59; S,6.60.

EXAMPLE 4 Preparation of2-(2-Dodecylphenyl)-2-[(1-sulfomethyl-5-tetrazolyl)thio]acetic acidammonium salt hydrate

The compound of Example 1(e) (200 mg, 0.57 mmol) and5-mercapto-1-sulfomethyltetrazole disodium salt (136 mg, 0.57 mmol) weredissolved in 4 ml of dimethylformamide and stirred at ambienttemperature overnight. The solvents were pumped off and the residuedissolved in 5 ml of water. A 1N solution of sodium hydroxide (2 ml, 2mmol) was added at 0° and the mixture stirred overnight at ambienttemperature. The solvents were pumped off and the residue flashchromatographed on 50 grams of silica gel eluted with 6:3:1 (methylenechloride: ethanol: ammonium hydroxide). The solvents were stripped andthe residue taken up in water and lyophilized to give the desiredcompound (180 mg 58%) as an amorphous white solid.

Analysis for C₂₂ H₃₄ N₄ O₅ S₂ 2NH₃ 3/2 H₂ O-- Calculated: C,47.21;H,7.74; N,15.01. Found: C,47.57; H,7.39; N 14.70.

EXAMPLE 5 Preparation of2[2-(8-Phenyloctyl)phenyl]-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]aceticacid dipotassium salt hydrate (a) 2-(8-Phenyloctyl)benzaldehyde

8-Phenyloctyl bromide was prepared from 8-phenyloctanol, carbontetrabromide and triphenylphosphine in methylene chloride. A solution of8-phenylocatanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml)was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 20°C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of theoctanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) inmethylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) inmethylene chloride (50 ml) and the resulting solution was stirred for2.5 hours. The volatiles were evaporated and the residue was taken up inether (100 ml), cooled in ice, and filtered. The filtrate was evaporatedand distilled to afford 8-phenyloctyl bromide as an oil. To8-phenyloctyl bromide and 21.27 mmol of magnesium) in distilledtetrahydrofuran (40 ml) was added2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmol) intetrahydrofuran (20 ml). After stirring for 24 hours, the reactionmixture was similarly worked up to yield2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solutionof the oxazoline (11.58 mmol) in methyl iodide (20 ml) was refluxedunder argon for 18 hours. Removal of the volatiles afforded thecorresponding 3,4,4-triimethyloxazolinium iodide as a white solid (mp76.5°-78° C.). To an ice cold solution of the iodide (9.46 mmol) inmethanol (35 ml) was added in portions sodium borohydride (9.20 mmol).Treatment of the reaction mixture as in Example 1(c) results in theisolation of the desired product as an oil.

Analysis for C₂₁ H₂₆ O: Calculated: C, 85.67; H, 8.90. Found: C, 85.12,85.22; H, 8.94, 8.96.

(b) Alternative preparation of 2-(8-phenyloctyl) benzaldehyde

A solution of 5-hexynyl alcohol (102 mmol) in pyridine (150 ml), underargon, was cooled to 0° C. and p-toluenesulfonyl chloride (204 mmol) wasadded. The reaction mixture was kept at about 4° C. for 18 hours, pouredinto ice-water and then taken up in ether. The ether extract was washedwith cold 10% hydrochloric acid, water and brine. The organic layer wasdried and concentrated in vacuo to give 5-hexynyl p-toluenesulfonate. Asolution of phenylacetylene (97 mmol) in tetrahydrofuran (200 ml)containing a trace of triphenylmethane was cooled to 0° C. and n-butyllithium (37.3 ml of 2.6 mol in hexane) was added dropwise. The resultingsolution was stirred at 0° C. for 10 minutes and hexamethylphosphoramide(21 ml) was added dropwise. After stirring for 10 minutes a solution of5-hexynyl p-toluenesulfonate (97.1 mmol) in tetrahydrofuran (200 ml) wasadded. The reaction mixture was stirred at room temperature for 18hours, diluted with ether and the organic layer was washed with waterand brine. The dried organic solution was concentrated and the productwas purified by flash chromatography to give 1-phenylocta-1,7-diyne. Amixture of this compound (43 mmol), 2-bromobenzaldehyde (35.8 mmol).cuprous iodide (0.5 mmol) and bis(triphenylphosphine) palladium (II)chloride (0.7 mmol) in triethylamine (100 ml) was heated in an oil bath(95° C.) for one hour. The reaction mixture was cooled to 0° C.,filtered and the filtrate was concentrated. The residue was dissolved inether, washed with 10% hydrochloric acid, water and brine. The organiclayer was dried and concentrated to give a product which was purified byflash chromatography to yield 2-(8-phenyl-1,7-octadiynyl)benzaldehyde. Asolution of this compound (24.1 mmol) in ethyl acetate (100 ml) and 10%palladium on charcoal (1 g) was hydrogenated (40 psi of hydrogen) atroom temperature for 15 minutes. The catalyst was filtered off and thefiltrate concentrated to give the 2-(8-phenyloctyl)benzaldehyde.

(c) Methyl 2-[2-(8-phenyloctyl)phenyl]-2-hydroxy acetate

The compound of Example 5(a) or 5(b) (10 mmol) was dissolved inmethylene chloride (10 ml) and stirred at 0° C. under argon. Zinc iodide(1.1 mmol) was added followed by the dropwise addition of trimethylsilylcyanide (1.47 ml, 11 mmol) dissolved in methylene chloride (20 ml).After 1 hour at 0° C. the ice bath was removed and the mixture stirredfor 1 hour at room temperature. The solvent was stripped and methanol(60 ml) was added at ice bath temperature. Excess hydrogen chloride wasbubbled into the solution while stirring. The ice bath was removed andthe mixture stirred at room temperature for 18 hours. Water (12 ml) wasadded and the mixture stirred for 2 hours. The solvent was evaporatedand the residue extracted with ethyl acetate, dried over anhydroussodium sulfate, filtered and evaporated. The crude product was flashchromatographed on 200 grams of silica gel with 20% ethyl acetate/hexaneas eluant to give the product as a clear colorless liquid.

(d) Methyl 2-chloro-2-[2-(8-phenyloctyl)phenyl]acetate

The compound of Example 5(c) (6.8 mmol) was stirred under argon in anice bath and thionyl chloride (15 ml) was added in a single portion. Theice bath was removed and the reaction mixture was stirred for 18 hours.The solvent was stripped and the residue flash chromatographed on 100grams of silica gel with 20% methylene chloride/carbon tetrachloride aseluant to give the product as a clear colorless liquid.

(e) Methyl2-[2-(8-phenyloctyl)phenyl]-2-[[1-(3-carboxylpropyl)-5-tetrazolyl]thio]acetate

The compound of Example 5(d) (744 mg, 2 mmol) was dissolved in methylenechloride (25 ml) and stirred under argon at room temperature.5-mercapto-1-(3-carboxypropyl)tetrazole (376 mg., 2 mmol) andtriethylamine (0.84 ml, 6 mmol) were dissolved in methylene chloride (25ml) and added to the solution of the compound of Example 5(d). Themixture was stirred under argon for 24 hours. The solvent was strippedand the residue was flash chromatographed on 100 grams of silica gelwith 70:30:1 hexane: ethyl acetate: formic acid as eluant to give thedesired product (830 mg, 79%).

(f)2-[2-(8-phenyloctyl)phenyl]-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]aceticacid.

The compound of Example 5(e) (524 mg, 1 mmol) was dissolved in methanol(12 ml) and stirred under argon in an ice bath, A 1N solution of sodiumhydroxide (4 ml, 4 mmol) was added dropwise, the ice bath removed, andthe mixture stirred overnight at room temperature. The solvent wasstripped and the residue was cooled in an ice bath and acidified withdilute hydrochloric acid. The crude product was extracted with ethylacetate, dried over anhydrous sodium sulfate, filtered, and evaporated.The crude product was flash chromatographed on 70 grams of silica geleluted with 30:70:1 ethyl acetate:hexane: formic acid followed by50:50:1 ethyl acetate:hexane:formic acid to eluent to give the desiredproduct (495 mg; 97%).

(g)2-[2-(8-Phenyloctyl)phenyl]-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]aceticacid, dipotassium salt, hydrate.

The compound of Example 5(f) (495 mg, 0.97 mmol) was treated with asolution of potassium carbonate (415 mg, 3 mmol) in 10 ml of water underargon at ice-bath temperature. The ice bath was removed and the mixtureallowed to stir for 15 minutes at room temperature. The solution wasthen chromatographed on a C₁₈ column; elution was with water to removethe excess base and then with 1:1 (acetonitrile:water). Lyophilizationgave the desired compound (524 mg, 92%) as a white hygroscopic solid.

Analysis for C₂₇ H₃₂ N₄ O₄ S 2 K H₂ O-- Calculated: C,53,62; H,5.67;N,9.26. Found: C,53.81; H,5.51; N,9.36.

Similarly the following compounds are prepared according to the generalmethod of Example 5 from 2-(2-methoxyphenyl)-4,4-dimethyloxazoline andthe appropriate alkyl halide;

2-[2-(4-phenylbutyl)phenyl]-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]aceticacid, dipotassium salt, hydrate; and

2-[2-(10-phenyldecyl)phenyl]-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]aceticacid, dipotassium salt, hydrate.

EXAMPLE 6 Preparation of3-(2-Dodecylphenyl)-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]propanoicacid (a) t-Butyl 3-hydroxy-3-(2-dodecylphenyl)propionate

A solution of diethylaluminum chloride (54.7 mmol) in hexane was addedto a slurry of zinc dust (74.5 mmol) and a catalytic amount of copper(I) bromide (2.5 mmol) in anhydrous tetrahydrofuran (300 ml) whilestirring under argon at 20° C. The resulting mixture was then cooled to0° C. in an ice-methanol bath. A solution of t-butyl bromoacetate (49.8mmol) and 2-dodceylbenzaldehyde of Example 1(c) (54.7 mmol); inanhydrous tetrahydrofuran was added slowly over 60 minutes. The reactionwas stirred for about 24 hours and was permitted to warm slowly to roomtemperature. The mixture was filtered to remove zinc, concentrated,acidified with 3N hydrochloric acid and extracted with ether. Organicextracts were dried over magnesium sulfate, filtered, and evaporated toafford crude product. This material was then flash chromatographed onsilica using 8% ethyl acetate in hexane to give the desired product in79% yield.

(b) 3-(2;-dodecylphenyl)-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]propanoicacid.

A 3 neck 100 ml round bottom flash equipped with a thermometer andstirring bar was cooled to -30° C. using a dry ice-acetone bath followedby an ice-methanol bath. The flask was charged with trifluoroacetic acid(20 ml) followed by 5-mercapto-1-(3-carboxypropyl)tetrazole (0.00128mol, 0.1923 g). The mixture was permitted to cool under argon for 10minutes. To this was added the compound of Example 6(a) (0.001282 mol.0.5 g), in methylene chloride (5 ml). The reaction was stirred for 2hours at 15° C. and was permitted to warm to ambient temperature. Thetrifluoroacetic acid was evaporated and the resulting oil waschromatographed on C₁₈ packing using 20% water in methanol with 1.0 %formic acid to yield the desired product.

Analysis for C₂₆ H₄₀ N₄ O₄ S-- Calculated: (with 0.5 mole H₂ O) C:60.81;H:7.79; N: 10.92. Found: C: 20.24; H: 7.79; N: 10.62.

Similarly, the following compounds are prepared according to the generalmethod of Example 6.

3-(2-tetradecylphenyl)-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]propanoicacid; and

3-(2-octylphenyl)-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thioπpropanoicacid.

EXAMPLE 7 Preparation of3-[2-(8-Phenyloctyl)phenyl]-3-[(1-carboxymethyl-5-tetrazolyl)thio]propanoicacid (a) t-Butyl 3-hydroxy-3-[2-(8-phenyloctyl)phenyl]propionate

A solution of diethylaluminum chloride (0.0082 moles, 8.2 ml) in hexanewas added to a slurry of zinc dust (0.0111 mol; 0.7248 g) and acatalytic amount of copper (I) bromide (0.0004 moll; 0.0585 g) inanhydrous tetrahydrofuran (40 ml) while stirring under argon at 20° C.The resulting mixture was then cooled to -20° C. in an ice-methanolbath. A solution of t-butyl bromoacetate (0.0082 mol; 1.32 ml) and2-(8-henyloctyl)benzaldehyde of Example 5(a) or (b) (0.0082 moles;2.3969 g) in anhydrous tetrahydrofuran was added slowly over 60 min. Thereaction was stirred overnight and was permitted to warm up slowly toroom temperature. The mixture was filtered to remove zinc, concentrated,and azeotroped with methylene chloride. The resulting oil was thenchromatographed on silica using 5% ethyl acetate in hexane with 0.5%formic acid to yield the desired product.

(b) Preparation of 3-[2-(8-phenyloctyl)phenyl]-3-[(1-carboxymethyl-5-tetrazolyl)thio]propanoic acid

A 3-neck 100 ml round bottom flash equipped with a thermometer andstirring bar was cooled to -30° C. using a dry ice-acetone bath followedby an ice-methanol bath. The flask was charged with trifluoroacetic acid(10 ml) followed by 5-mercapto-1-carboxymethyltetrazole (0.00124 mol,0.2 g). The mixture was permitted to cool under argon for 10 minutes. Tothis mixture was added the compound of Example 7(a) (0.00113 mol, 0.4634g, in methylene chloride (3 ml). The reaction was stirred for 2 hours at-15° C. and was then permitted to warm to room temperature. Thetrifluoroacetic acid was evaporated and azeotroped with methylenechloride. The resulting oil was chromatographed using 30% ethyl acetatein hexane with 0.5% formic acid to provide a 26% yield of desiredproduct.

Analysis for C₂₆ H₃₂ N₄ O₄ S.3/4H₂ O-- Calculated: C:61.21; H;6.32;N:10.98; S:6.29; Found: C:61.22; H:6.47; N:11.87; S:6.38

Similarly, the following compounds are prepared according to the generalmethod of Example 7:

3-[2-(4-phenylbutyl)phenyl]-2-[(1-carboxypropyl-5-tetrazolyl)thio]propanoicacid; and

3-[2-(10-phenylbutyl)phenyl]-2-[(1-carboxypropyl-5-tetrazolyl)thio]propanoicacid.

EXAMPLE 8 Preparation of3-[2-(8-Phenylbutyl)phenyl]-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]propanoicacid

A 3-neck 100 ml round bottom flask equipped with a thermometer andstirring bar was cooled to -30° C. using a dry ice-acetone bath followedby an ice-methanol bath. The flash was charged with trifluoroacetic acid(20 ml) followed by 5-mercapto-1-(3-carboxylpropyl)tetrazole (0.0024mol, 0.4574 g). The mixture was permitted to cool under argon for 10minutes. To this was added the compound of Example 7(a) (0.0024 mol,0.9069 g) in methylene chloride (5 ml). The reaction was stirred for 2hours at -15° C. and then was permitted to warm to room temperature. Thetrifluoroacetic acid was evaporated and the resulting oil waschromatographed on reverse phase C₁₈ packing using 20% water in methanolwith 0.5% formic acid to give the desired product in 26% yield.

Analysis for C₂₈ H₃₆ N₄ O₄ S. 1/2 H₂ O-- Calculated: C:63.02; H:6.80;N:10.5. Found: C:63.08; H:6.74; N:10.4

EXAMPLE 9 Preparation of2-(2-Undecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]acetic acid(a) 2-Undecyloxybenzaldehyde

To a stirred suspension of sodium hydride (10.0 mmol), which wasprewashed with petroleum ether, in sieve dried dimethylformamide (10 ml)was added dropwise a solution of salicylaldehyde (10.1 mmol) indimethylformamide (1 ml)'. To the reaction mixture was then addedundecyl bromide (10.0 mmol) and the mixture stirred for 16 hours atambient temperature under nitrogen. The reaction mixture was taken up inhexane (50 ml) and washed with 10 percent sodium hydroxide (2×50 ml) andsaturated sodium chloride (50 ml). The organic phase was dried overanhydrous magnesium sulfate and charcoal. Evaporation of the volatilesyielded a colorless liquid which was purified by flash chromatographyover silica gel with 2 percent ethyl acetate in hexane as eluant toafford the desired product as an oil.

Analysis for C₁₈ H₂₈ O₂ : Calculated: C, 78.21; H, 10.21. Found: C,77.92; H. 9.95.

(b) 2-(2-Undecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid

Employing the general methods of Example 1(d)-1(g, the compound ofExample 9(a) is converted to the desired product.

The following compounds are prepared according to the general methodsdescribed above from the appropriately substituted hydroxybenzaldehydeand the appropriate alkyl halide:

2-(2-Heptyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]acetic acid;

2-(2-Dodecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid;

2-(5-Methoxy-2-dodecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid;

2-(5-Methyl-2-dodecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid;

2-(5-Fluoro-2-dodecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid;

2-(5-Chloro-2-dodecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid;

2-(5-Iodo-2-dodecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid;

2-(5-Bromo-2-dodecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid;

2-(5-Hydroxy-2-dodecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid;

2-(5-Nitro-2-dodecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid;

2-(5-Amino-2-dodecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid;

2-(5-Trifluoromethyl-2-dodecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid;

2-(2-Dodecylthiophenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]aceticacid is prepared from 2-(dodecylthio)benzaldehyde.

2-(2-Heptylthiophenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]acetic acidis prepared from 2-(heptylthio)benzaldehyde.

EXAMPLE 10 Preparation of2-[2-6-Phenylhexyloxy)phenyl]-2-[[1-(3-carboxypropyl-5-tetrazolyl)thio]aceticacid a) a) 2-(6-Phenylhexyloxy)benzaldehyde

A solution of 6-phenylhexanoic acid (19.8 mmol) in sieve driedtetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30ml, 29.1 mmol) at 0° C. for 4 hours to give 6-phenylhexanol. To an icecold solution of the hexanol (ca. 19.8 mmol) and carbon tetrabromide(21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine(22.30 mmol) in methylene chloride (50 ml) and the resulting solutionwas stirred for 2.5 hours. The volatiles were evaporated and the residuewas taken up in ether (100 ml), cooled in ice, and filtered. Thefiltrate was evaporated and distilled to afford 6-phenylhexyl bromide asan oil. A mixture of the bromide (8.00 mmol), salicylaldehyde (8.19mmol) and potassium carbonate (9.33 mmol) in dimethylformamide (10 ml)was heated to 100° C. and maintained at that temperature for one hour.The cooled reaction mixture was taken up in hexane (50 ml) and washedwith 5% sodium hydroxide (50 ml) and saturated sodium chloride (50 ml).The organic phase was dried over anhydrous magnesium sulfate andcharcoal. Evaporation yielded a colorless oil which was purified byflash chromatography over silica gel with 5% ethyl acetate in hexane aseluant to afford the desired product as an oil.

Analysis for C₁₉ H₂₂ O₂ : Calculated: C, 80.82; H, 7.85. Found: C,80.62; H, 7.72.

(b)2-[2-(6-Phenylhexyloxy)phenyl]-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]aceticacid

Employing the general methods of Example 5(c) through 5(g) the compoundof Example 10(a) is converted to the desired product.

The following compounds are prepared according to the general methodsdescribed above from the appropriately substituted phenylalkyloxybenzaldehyde.

2-[2-(3-Phenylpropyloxy)phenyl]-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]aceticacid; and

2-[2-(9-Phenylnonyloxy)phenyl]-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]aceticacid.

EXAMPLE 11 Preparation of2-Methyl-3-(2-dodecylphenyl)-3-[(1-carboxymethyl-5-tetrazolyl)thio]propanoicacid (a) Methyl 2-methyl-3-hydroxy-3-(2-dodecylphenyl)propanoate

To a suspension of zinc dust (15 mmol) and copper (I) bromide (5 mmol)in distilled tetrahydrofuran (10 ml) at 25° C. was added diethylaluminumchloride (10 mmol). The mixture was stirred for 5 minutes, then cooledto 0° C. in an ice-methanol bath. A solution of the compound of Example1(c) (10 mmol) and methyl dl-2-bromopropionate (10 mmol) intetrahydrofuran (10 ml) was added dropwise to the cold suspension. Theresulting mixture was stirred for 3 hours at 25° C. The reaction mixturewas filtered and the filtrate was washed with water, dried overmagnesium sulfate, and evaporated to give the product.

(b)Methyl-3-(2-dodecylphenyl)-3-[(1-carboxymethyl-5-tetrazolyl)thio]propanoat

To a solution of trifluoroacetic acid (15 ml) and5-mercapto-1-carbethoxymethyltetrazole (2.4 ml) at 0° C. is added thecompound of Example 11(a). The reaction mixture stirred for 3 hours andevaporated. The resulting residue is flash chromatographed on silica,and eluted with 20% ethyl acetate in hexane, to give the product.

(c)2-Methyl-3-(2-dodecylphenyl)-3-[(1-carboxymethyl-5-tetrazolyl)thio]propanoicacid

To a solution of 10% sodium hydroxide (50 ml), methanol (12 ml) andethylene glycol dimethyl ether is added the compound of Example 12(b)(93.9 mmol). The mixture is stirred for 24 hours at 25° C. The reactionmixture is then cooled in an ice-methanol bath to 0° C. and is acidifiedwith hydrochloric acid to pH 3.5, is extracted with diethyl ether, isdried over magnesium sulfate, filtered and evaporated. The resultingmixture of isomers is flash chromatographed on silica, and eluted with30% ethyl acetate in hexane, to give the product.

EXAMPLE 12 Preparation of2-(2-dodecylphenyl)-2-[2-(tetrazol-5-yl)ethylthio]acetic acid (a)5-(2-Mercaptoethyl)tetrazole

To 100 ml of tetrahydrofuran at 0° was added aluminum chloride (6.65 g,0.05 mol) and sodium azide (9.75 g, 0.15 mol). This mixture was allowedto come to 22°, and stirred 30 minutes. β-Mercaptopropionitrile (4.35 g,0.05 mol) was added, and the mixture heated to reflux for 24 hr. Themixture was cooled, acidified carefully with excess 15% aqueoushydrochloric acid, and the solvents removed under reduced pressure. Theresidue was extracted with ethyl acetate, the extracts washed withwater, dried, and the solvent evaporated. The residue was recrystallizedfrom 1,2-dichloroethane, and gave 3.7 g (57%) of5-(2-mercaptoethyl)tetrazole.

(b) Methyl-2-(2-dodecylphenyl)-2-[2-(tetrazol-5-yl)ethylthio]acetate

A mixture of methyl 2-chloro-2-(2-dodecylphenyl)acetate (0.615 g, 1.75mmol), 5-(2-mercaptoethyl)tetrazole (0.227 g, 1.75 mmol), andtriethylamine (0.48 ml, 3.5 mmol) in 20 ml of methylene chloride wasstirred 18 hours at 22° and the solvent was evaporated. The residuetaken up in diethyl ether, washed with 1N hydrochloric acid, dried andthe solvent removed. The residue was chromatographed over a silica gelcolumn. Impurities were eluted with ethyl acetate/hexane (1:3), and theproduct was eluted with methanol/ethyl acetate (1:19). Evaporation ofthe solvents from these functions gave the desired product, 0.570 g(73%).

(c) 2-(2-Dodecylphenyl)-2-[2-(tetrazol-5-yl)ethylthio]acetic acid

A stirred suspension of methyl2-(2-dodecylphenyl)-2-[2-(tetrazol-5-yl)ethylthio]acetate (0.57 g, 1.28mmol) in 10 ml of methanol and 8 ml of water at 70° was treated with 3ml of 2.5N sodium hydroxide. After 30 minutes at 70°, the mixture wascooled, diluted with 10 ml of water and filtered. The filtrate wasacidified, extracted with ethyl acetate, and the extracts were dried andthe solvente evaporated. The residue was recrystallized from methanoland gave the desired product 0.415 g (74%). NMR (CDCl₃ /Me₂ CO):10.23-11.70 (broad, 2H), 7.52-7.62 (m,1H), 7.27 (s,3H), 5.04 (s,1H),3.0-3.44 (m,4H), 2.63-2.92 (t,2H), 1.12-1.84 (m,20H), 0.62-1.02 (t,3H).

EXAMPLE 13 Preparation of3-[2-(8-phenyloctyl)phenyl]-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]-2-hydroxypropanoicacid (a) 2(8-Phenyloctyl)benzaldehyde

2-(8-phenyloctyl)benzaldehyde was prepared as described in Example 5(a)or (b).

(b) Methyl 3-[2-(8-Phenyloctyl)phenyl]-2,3-epoxypropionate

The compound of Example 7(a) (2.94 g, 10 mmol) was dissolved in diethylether (25 ml) and the solution was stirred under argon at 0° C. Methylchloroacetate (1.32 ml, 15 mmol) was added, followed by the addition ofsodium methoxide (810 mg, 15 mmol). The mixture was stirred for 2.5hours at ice bath temperature. A small quantity of water was added, theether phase separated, dried over anhydrous sodium sulfate, filtered andevaporated. The residue was flash chromatographed on 80 grams of silicagel eluted with 5-30% ethyl acetate/hexane to give the product.

(c)Methyl-3-[2-(8-phenyloctyl)phenyl]-3-[[1-(3-carboxypropyl-5-tetrazolyl]thio]-2-hydroxyproponate

The compound of Example 13(c) (549 mg, 1.5 mmol) was dissolved inmethanol (6 ml) containing 2% triethylamine and the solution was stirredunder argon at room temperature. The5-mercapto-1-(3-carboxypropyl)tetrazole tetrazole (282 mg, 1.5 mmol) andtriethylamine (0.84 ml, 6 mmol) were dissolved in methanol (9 ml) andadded dropwise to the reaction mixture which was then stirred for 5 dayat room temperature. The solvent was stripped and the residue was flashchromatographed on 50 grams of silica gel eluted with 70:30:1(hexane:ethyl acetate:formic acid) to give the desired product.

(d)3-[2-(8-phenyloctyl)phenyl]-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]-2-hydroxypropanoicacid

The compound of Example 13(d) (554 mg, 1 mmol) was dissolved in methanol(15 ml) and stirred under argon at ice bath temperature. A 1N solutionof sodium hydroxide (4 ml, 4 mmol) was added dropwise, the ice bathremoved and the mixture stirred at room temperature overnight. Themethanol was stripped and the residue acidified with dilute hydrochloricacid. Extraction with ethyl acetate followed by drying over anhydroussodium sulfate, filtration and evaporation gave the crude product whichwas flash chromatographed on 25 grams of silica gel eluted with50:50:1(ethyl acetate:hexane:formic acid) to give the desired product.

EXAMPLE 14 Preparation of3-[2-(8-phenyloctyl)phenyl]-3-[(1-carboxymethyl-5-tetrazolyl)thio]-2-hydroxypropanoicacid (a) Methyl 2,3-epoxy-3-[2-(8-phenyloctyl)phenyl]propanoate

2-(8-phenyloctyl)benzaldehyde prepared as in Example 5(a) or (b) (15 g)was dissolved in methylene chloride (58 ml) under an argon atmosphere at25° C. Methyl chloroacetate (6.2 ml) was added in one portion. Theresulting solution was cooled to -28° C. using a dry ice/isopropanolbath. Sodium methoxide (13.5 ml) was then added slowly, maintainingtemperature between -28° C. to -15° C. The reaction mixture was thenstirred for 45 minutes, and permitted to warm slowly to 0° C. Thereaction was then stirred for 1.5 hours at 0° C. The reaction mixturewas quenched with a solution (117 ml) of aqueous buffer (pH 7) and 117ml of hexane. The layers were separated, the aqueous portion wasfiltered and washed with hexane. The combined organic extracts weredried over sodium sulfate, filtered and concentrated. The residue wasflash chromatographed on silica and eluted with 3:97 ethylacetate/hexane to give the desired product.

(b) Methyl 2-hydroxy-3-[(1-carboxymethyl-5-tetrazolyl)thio]propanoate

The methyl 2,3-epoxy-3-[2-(8-phenyloctyl)phenyl]propanoate (0.4 g) ofExample 14(a) was dissolved in 5 ml of methanol containing 2%triethylamine under an argon atmosphere. The reaction mixture was cooledusing an ice/methanol bath. A solution of 0.205 g of5-mercapto-1-carbethoxymethyltetrazole and 0.61 ml of triethylamine in 5ml of methanol containing 2% triethylamine was added. The bath wasremoved and the reaction was permitted to warm to room temperature. Thereaction was concentrated and flash chromatographed on silica with 20%ethyl acetate/hexane as eluant to give the desired product.

(c)3-[2-(8-phenyloctyl)phenyl]-3-[(1-carboxymethyl-5-tetrazolyl)thio]-2-hydroxypropanoic acid

The methyl 2-hydroxy-3-[(1-carboxymethyl-5-tetrazolyl)thio]propanoate(0.45 g) of Example 14(b) was dissolved in methanol (6.6 ml) was cooledwith an ice and methanol bath to which was added 3.3 ml of a 4% solutionof sodium hydroxide. The bath was removed and reaction permitted to warmto room temperature overnight. The methanol was then stripped, and theresidue was diluted with dilute hydrochloric acid. Extraction with ethylacetate was followed by drying over magnesium sulfate, filtration, andevaporation. The crude product was flash chromatographed on silica with30-50% ethyl acetate/hexane. The column was washed with 100% methanol.40 mg of desired product was recovered.

EXAMPLE 15 Preparation of2-(2-Dodecylphenyl)-2-(5-carboxy-4-methyl-2-thiazolylthio)acetic acid(a) Methyl2-(2-Dodecylphenyl)-2-(5-carbomethoxy-4-methyl-2-thiazolylthio)acetate

A mixture of 0.53 g (0.0015 mol) of the compound of Example 1(e), 0.39 g(0.00195 mol) of methyl 4-methyl-2-mercaptothiazole-5-carboxylate, 0.23g (0.0023 moles) of triethylamine and 10 ml of methylene chloride werestirred under argon at room temperature for 48 hours. The reactionmixture was washed 3 times with 5 ml of 5% sodium carbonate solutionfollowed by water, dried over magnesium sulfate, filtered andconcentration under vacuum. The oily residue was flash chromatographedusing hexane--5% ethyl acetate yield 0.58 g of oil.

(b) 2-(2-Dodecylphenyl)-2-(5-carboxy-4-methyl-2-thiazolylthio)aceticacid.

A mixture of 0.24 g (0.0046 mol) of the compound of Example 15(a), 0.11g (0.0028 mol) of sodium hydroxide, 10 ml of methanol and 1 ml of waterwere stirred at room temperature and under argon for 2 days. Thereaction mixture was concentrated under vacuum and the residual oil wasredissolved in 5 ml of water. The aqueous solution was adjusted to pH3.83 with dilute phosphoric acid or until a cloudy solution wasobtained; and then was extracted 3 times with 10 ml of ethyl acetate.The extracts were washed with 5 ml of water, dried over magnesiumsulfate, filtered and concentrated. The oily residue obtained wastriturated with petroleum ether. The desired product (0.054 g) wasobtained as a powder having a m.p. 88°-91° C.

Analysis for C₂₅ H₃₅ NO₄ S₂ : Calculated: C:62.86; H:7.38; N:2.93;Found: C:62.59; H:7.47; N:2.88.

EXAMPLE 16 Preparation of2-[2-(8phenyloctyl)phenyl]-2-[[2-carboxy-5-(1,3,4-thiadiazolyl)thio]aceticacid (a) Methyl2-[2-(8-phenyloctyl)phenyl]-2-[[2-carbethoxy-5-(1,3,4-thiadiazolyl)]thio]acetate

The compound of Example 5(d) (744 mg, 2 mmol) is dissolved in 25 ml ofmethylene chloride and stirred under argon at room temperature. Ethyl5-mercapto-1,3,4-thiadiazole-2-carboxylate (380 mg, 2 mmol) andtriethylamine (0.84 ml, 6 mmol) is dissolved in 25 ml of methylenechloride and added to the solution of the compound of Example 5(d). Themixture is stirred under argon for 48 hours. The solvent is evaporated,and the residue is flash chromatographed on silica gel eluted with ethylacetate/hexane to give the product.

(b)2-[2-(8-phenyloctyl)phenyl]-2-[[2-carboxy-5-(1,3,4-thiadiazolyl)thio]aceticacid

The compound of Example 16(a) (526 mg, 1 mmol) is dissolved in 10 ml ofmethanol and stirred under argon in an ice bath. A 1N solution of sodiumhydroxide (4 ml, 4 mmol) is added. The ice bath is removed and themixture is stirred for 24 hours at room temperature. The solvent isevaporated, the residue cooled in an ice bath, acidified with dilutehydrochloric acid, extracted with ethyl acetate, dried over anhydroussodium sulfate, filtered and evaporated to give the product.

EXAMPLE 17 Preparation of2-[2-(8-phenyloctyl)phenyl]-2-[(2-carboxy-5-furfuryl)thio]acetic acid(a) Methyl2-[2-(8-phenyloctyl)phenyl]-2-[(2-carboxy-5-furfuryl)thio]acetate

The compound of Example 5(d) (744 mg, 2 mmol) is dissolved in 25 ml ofmethylene chloride and stirred under argon at room temperature.5-mercaptomethylfuric acid (316 mg, 2 mmol) and triethylamine (0.84 ml,6 mmol) is dissolved in 25 ml of methylene chloride and added to thesolution of the compound of Example 5(d). The mixture is stirred underargon for 48 hours. The solvent is evaporated, and the residue is flashchromatographed on silica gel eluted with ethyl acetate/hexane/formicacid to give the product.

(b) 2-[2-(8-phenyloctyl)phenyl]-2-[(2-carboxy-5-furfuryl)thio]aceticacid

The compound of Example 17(a) (494 mg, 1 mmol) is dissolved in 10 ml ofmethanol and stirred under argon in an ice bath. A 1N solution of sodiumhydroxide (4 ml, 4 mmol) is added. The ice bath is removed and themixture is stirred for 24 hours at room temperature. The solvent isevaporated, the residue cooled in an ice bath, acidified with dilutehydrochloric acid, extracted with ethyl acetate, dried over anhydroussodium sulfate, filtered and evaporated to give the product.

EXAMPLE 18 Preparation of3-[2-(6-thiophenoxyhexylthio)phenyl]-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]-2-hydroxypropanoicacid a) Preparation of 2-(6-thiophenoxyhexylthio)benzoic acid

Thiosalicylic acid (1.2 g, 0.008 mole) and 6-thio-phenoxyhexylbromide(2.5 g, 0.009 mole) are dissolved in dimethylformamide (50 ml) and thesolution is stirred under argon. Potassium carbonate (1.5 g, 0.011 mole)is added carefully to the reaction. After the addition is complete themixture is slowly warmed to 100° C. The solvents were evaporated, andthe residue is dissolved in water, acidified with dilute hydrochloricacid, extracted with ethyl acetate, dried over anhydrous sodium sulfate,filtered, and evaporated. The residue is flash chromatographed on silicagel to give the desired product.

(b) Preparation of 2-(6-thiophenoxyhexylthio)benzyl alcohol

To a suspension of lithium aluminum hydride (0.292 g, 0.007 mole) intetrahydrofuran (30 ml) is added a solution of2-(6-thiophenoxyhexylthio)benzoic acid (2.42 g, 0.007 mole) intetrahydrofuran (30 ml). The reaction is conducted as in Example 1b).

(c) Preparation 2-(6-thiophenoxyhexylthio)benzaldehyde

To a suspension of manganese dioxide (11.78 g, 0.135 mole) in ethylacetate (30 ml) is added a solution of 2-(6-thiophenoxyhexylthio)benzylalcohol (1.23 g; 0.0037 mole) in ethyl acetate (20 ml). The reaction isconducted as in Example 1c).

(d) Methyl 3-[2-(6-thiophenoxyhexylthio)phenyl]-2,3-epoxypropionate

The compound of Example 18(c) (10 mmol) is dissolved in diethyl ether(25 ml) and the solution is stirred under argon at 0° C. Methylchloroacetate (15 mmol) is added followed by the addition f sodiummethoxide (15 mmol). The mixture is stirred for 2.5 hours at ice bathtemperature. A small quantity of water is added, the ether phase isseparated, dried over anhydrous sodium sulfate, filtered, andevaporated. The residue is flash chromatographed on 80 grams of silicagel eluted with 5-30% ethylacetate/hexane to give the product.

(e) Methyl3-[2-(6-thiophenoxyhexylthio)phenyl]-3-[[1-(3-carboxypropyl-5-tetrazolyl]thio]-2-hydroxypropionate

The compound of Example 18(d) (1.5 mmol) is dissolved in methanol (6 ml)containing 2% triethylamine and the solution is stirred under argon atroom temperature. 5-Mercapto-1-(3-carboxypropyl)tetrazole (1.5 mmol) andtriethylamine (6 mmol) are dissolved in methanol (9 ml) and are addeddropwise to the reaction mixture which is then stirred for 5 days atroom temperature. The solvent is stripped and the residue is flashchromatographed on 50 grams of silica gel eluted with 70:30:1(hexane:ethyalcetate:formic acid) to give the desired product.

f)3-[2-(6-thiophenoxyhexylthio)phenyl]-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]-2-hydroxypropanoic

The compound of Example 18(e) (1 mmol) is dissolved in methanol (15 ml)and is stirred under argon at ice bath temperature. A 1N solution ofsodium hydroxide 94 mmol) is added dropwise, the ice bath is removed andthe mixture is stirred at room temperature overnight. The methanol isstripped and the residue is acidified with dilute hydrochloric acid.Extraction with ethyl acetate followed by drying over anhydrous sodiumsulfate, filtration, and evaporation gives the crude product which isflash chromatographed on 25 grams of silica gel eluted with 50:50:1(ethyl acetate:hexane:formic acid) to give the desired product.

EXAMPLE 19

As a specific embodiment of a composition of this invention, an activeingredient, such as the compound of Example 4, 13, or 14 is dissolved inisotonic saline at a concentration of 1 to 10 mg/ml and aerosolized froma nebulizer operating at an air flow adjusted to deliver the desiredaerosolized weight of drug.

EXAMPLE 20

As an additional embodiment of a composition of this invention 100 to1000 mg of an active ingredient, such as the compound of Example 4, 13,or 14 is combined with 4 mg of chlorpheniramine maleate with a suitablecarrier or excipient.

What is claimed is:
 1. A compound of formula (I) ##STR19## wherein q is 0, 1 or 2;R₁ is (L)_(a) --(CH₂)_(b) --(T)_(c) --B wherein a is 0 or 1, b is 3 to 14; c is 0 or 1; L and T are independently oxygen, sulfur or CH₂ with the proviso that L and T are not sulfur when q is 1 or 2; and B is C₁₋₄ alkyl, ethynyl, trifluormethyl, isopropenyl, furanyl, thienyl, cyclohexyl, or phenyl optionally monsubstituted with Br, Cl, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylthio, or thrifluoromethylthio; R₂ and A are independently selected from the H, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, F, Cl, Br, I, OH, NO₂ or NH₂ ; or R₁ and A are H and R₂ is (L).sub.(a) --CH₂)_(b) --(T)_(c) --B wherein a, b, c, L, T, and B are defined above; Y is (CHX)_(n) (CH₂)_(p) --Z wherein R₃ is OH, NH₂, aryloxy or C₁₋₆ alkoxy; n is 0 or 1; p is 0, 1; X is H, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, or F; and Z is COR₃ ; R is ##STR20## m is 0 to 6, but m is 1 to 6 when W is imidazole; R₄ and R₅ are independently hydrogen or C₁₋₄ alkyl at any position when m is not 0; W is tetrazolyl unsubstituted or substituted with one to three ##STR21## R₄ and R₅ are as defined above; j is 0 to 6; and V is hydrogen, C₁₋₄ alkyl, COR₃, SO₃ H, SO₂ H, SO₂ NH₂, COCH₂ OH, CHOHCH₂ OH, or tetrazolyl, with R₃ as defined above; or a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1 wherein Y is COOH.
 3. A compound of claim 2 wherein R₁ is C₈ to C₁₄ alkyl or phenyl C₄ to C₁₀ alkyl.
 4. A compound of claim 3 which is 2-(2-dodecylphenyl)-2-[(1-methyl-5-tetrazolyl)thio]acetic acid, or a pharmaceutically acceptable salt thereof.
 5. A compound of claim 3 which is 2-(2-dodecylphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]acetic acid, or a pharmaceutically acceptable salt thereof.
 6. A compound of claim 3 which is 2-(2-dodecylphenyl)-2-[[1-(3-carboxypropyl)-5-tetrazolyl)thio]acetic acid, or a pharmaceutically acceptable salt thereof.
 7. A compound of claim 3 which is 2-(2-dodecylphenyl)-2-[(1-sulfomethyl-5-tetrazolyl)thio]acetic acid, or a pharmaceutically acceptable salt thereof.
 8. A compound of claim 3 which is 2-[2-(8-phenyloctyl)phenyl]-2-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]acetic acid, or a pharmaceutically acceptable salt thereof.
 9. A compound of claim 3 which is 2-(2-dodecylphenyl)-2-[2-(tetrazol-5-yl)ethylthio]acetic acid, or a pharmaceutically acceptable salt thereof.
 10. A compound of claim 1 wherein Y is CH₂ COOH.
 11. A compound of claim 10 wherein R₁ is C₈ to C₁₄ alkyl or phenyl C₄ to C₁₀ alkyl.
 12. A compound of claim 11 which is 3-(2-dodecylphenyl)-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]propanoic acid, or a pharmaceutically acceptable salt thereof.
 13. A compound of claim 11 which is 3-[2-(8-phenyloctyl)-phenyl]-3-[(1-carboxymethyl-5-tetrazolyl)thio]propanoic acid, or a pharmaceutically acceptable salt thereof.
 14. A compound of claim 11 which is 3[2-(8-phenyloctyl)-phenyl]-3-[[1-(3-carboxypropyl)-5-tetrazolyl)thio]propanoic acid, or a pharmaceutically acceptable salt thereof.
 15. A compound of claim 1 wherein Y is CH(OH)COOH.
 16. A compound of claim 15 which is 3-[2-(8-phenyloctyl)phenyl]-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]-2-hydroxypropanoic acid, or a pharmaceutically acceptable salt thereof.
 17. A compound of claim 15 which is 3-[2-(8-phenyloctyl)phenyl]-3-[(1-carboxymethyl-5-tetrazolyl)thio]-2-hydroxypropanoic acid, or a pharmaceutically acceptable salt thereof.
 18. A pharmaceutical composition comprising a pharmaceutical carrier or diluent and a nontoxic amount of the compound claim
 1. 19. A pharmaceutical composition according to claim 18 in the form of an aerosol formulation or a sterile solution, or in a form suitable for administration by inhalation, parenteral administration, or topical administration.
 20. A pharmaceutical composition according to claim 19 in which the active ingredient is 3[2-(8-phenyl-octyl)phenyl]-3-[[1-(3-carboxypropyl)-5-tetrazolyl]thio]-2-hydroxypropanoic acid, or a pharmaceutically acceptable salt thereof.
 21. A pharmaceutical composition according to claim 19 in which the active ingredient is 3-[2-(8-phenyloctyl)phenyl]-3-[(1-carboxymethyl-5-tetrazolyl)thio]-2-hydroxypropanoic acid.
 22. A pharmaceutical composition according to claim 19 in which the active ingredient is 2-(2-dodecylphenyl)-2-[[1-(3-carboxypropyl-5-tetrazolyl]thio]acetic acid.
 23. A pharmaceutical composition comprising a pharmaceutical carrier or diluent and nontoxic amounts of a compound of claim 1, and an histamine H₁ -receptor antagonist.
 24. A method for inhibiting the effects of leukotriene comprising administration of an effective amount of the composition of claim
 20. 25. A method for inhibiting antigen-induced respiratory anaphylaxis comprising administration of an effective amount of the composition of claim
 24. 